Heretofore, in carrying out various organic synthetic reactions, it has been common to protect an alcoholic hydroxyl group in a raw material compound in an inactive form. Usually, such “protection” is carried out by directly bonding a compound so-called a protective group to an alcoholic hydroxyl group to be inactivated. After completion of the necessary reaction, the compound bonded to the hydroxyl group is disconnected, whereby the protected hydroxyl group is freed to be in an initial state. This operation is “deprotection”.
A t-butyldimethylsilyl group (TBS group) is known as a protective group which makes protection and deprotection possible under a relatively mild condition.
Known as a method for protection by a TBS group is, for example, a method of reacting t-butyldimethylchlorosilane and imidazole to an alcohol at room temperature in a dimethylformamide solvent, or a method of reacting t-butyldimethylchlorosilane and lithium sulfide to an alcohol at room temperature in an acetonitrile solvent, whereby the alcohol can be easily converted to a TBS ether under a mild condition. Here, the TBS ether is meant for the alcohol protected by a t-butyldimethylsilyl group (TBS group).
The TBS ether is stable under a basic condition and inert to a reaction with e.g. an alcoholate or enolate, a nucleophile such as lithium aluminum hydride, an organic metal compound such as n-butyl lithium, a Grignard reagent or lithium hexamethyldisilazide, or an oxidizing agent such as chromic acid, and therefore, it is widely used as a protective group for an alcohol in a reaction such as an aldol reaction, a Wittig reaction or a Swern oxidation. Particularly, it is very useful as a protective group for compounds which are unstable to an acid, among natural products, their derivatives, intermediates, etc. Such natural products include, for example, antibiotic substances such as β-lactam, macrolide, etc., lipid-related substances such as prostaglandin, leukotriene, etc., nucleic acid and sugars, anticancer drugs such as taxanes, furaquinocins, etc., ginkgolide, palytoxin, etc., and they are used, for example, in their derivatives or intermediates in many cases.
Deprotection methods for a TBS group are summarized in Non-patent Document 1. Common deprotection methods for a TBS group are broadly classified into a method by means of fluoride ions and a method by means of an acid (such as a Bronsted acid or a Lewis acid). As other methods, examples are reported wherein N-bromosuccinimide, diisobutyl aluminum hydride or a palladium complex is employed, but none of them is a method having substrate generality.
The deprotection method by means of fluoride ions may, for example, be a method of employing hydrofluoric acid, a method of employing an amine complex of hydrogen fluoride, such as pyridine-nHF or triethylamine-nHF, a method of employing an inorganic salt such as cesium fluoride, potassium fluoride, lithium borofluoride (LiBF4) or ammonium fluoride, or a method of employing an organic salt such as tetrabutylammonium fluoride (TBAF). However, hydrofluoric acid is highly toxic and is therefore not easy to handle. The amine complex of hydrogen fluoride is better in safety than hydrofluoric acid, but it still has a possible danger of releasing hydrofluoric acid and is lower than hydrofluoric acid in the ability as a deprotecting agent, and its price is also high. The inorganic fluoride salt has a low solubility in an organic solvent which is usually used in the deprotection, and its ability as a deprotecting agent is also not sufficient.
Tetrabutylammonium fluoride (TBAF) is superior to other deprotecting agents having fluoride ions in the safety, the solubility in an organic solvent and the ability as a deprotecting agent, and it is therefore frequently used in deprotection to remove a TBS group.
However, if TBAF is employed, a large amount of an ammonium salt will remain after the reaction, and for its removal, it is necessary to add water and carry out extraction and washing. This operation becomes to be a very cumbersome step particularly when the production is in a large scale and thus, is not suitable for the production in a large scale.
In order to avoid such an extraction and washing step after the deprotection, in Non-patent Document 2, the ammonium salt is removed by adding an ion exchange resin and calcium carbonate to the reaction solution after deprotecting the alcoholic hydroxyl group by means of TBAF, to have TBAF and other ammonium salts ion-bonded to the ion exchange resin, followed by filtration. However, this method requires filtration instead of the extraction and washing step.
Further, TBAF is a basic compound and its fluoride ions have nucleophilicity, whereby it has a drawback such that it cannot be used for a compound which is weak under a basic condition or a compound which is reactive with a nucleophile. Further, TBAF has such a nature that it is difficult to deprotect a TBS ether which is sterically crowded, whereby it frequently requires a high temperature and a long time for deprotection of a TBS ether of e.g. a secondary alcohol.
On the other hand, in the deprotection by means of a Bronsted acid or a Lewis acid, it is considered that an oxygen atom of an alcohol protected by TBS will be coordinated to the proton or Lewis acid, and the TBS group will be removed. Accordingly, the deprotection speed depends largely on the strength and concentration of the acid to be used. Principal protonic acids to be used for deprotection to remove a TBS group as disclosed in Non-patent Document 1 are as follows. Here, a numeral in brackets represents pKa (in water) as an index showing the strength of the acid, and the smaller the numeral, the stronger the acid. In the case of a so-called polybasic acid having a plurality of ionizable active hydrogen, pKa based on the first stage acid dissociation constant (Ka) is disclosed. Trifluoromethanesulfonic acid (−14), hydrochloric acid (−8), sulfuric acid (−3), methanesulfonic acid (−3), p-toluenesulfonic acid (−1), an ion exchange resin having a p-toluenesulfonic acid group at its terminal, trifluoroacetic acid (0.2), periodic acid (1.6), hydrofluoric acid (3.2), formic acid (3.8), acetic acid (4.8). According to Non-patent Document 1, an alcohol protected by a TBS group is deprotected (high reactivity) in an aqueous solution having a pH of at most 4, but is not deprotected (low reactivity) in an aqueous solution having a pH of more than 4. Deprotection to remove a TBS group will be easy by using a strong acid such as trifluoromethanesulfonic acid, but in the case of deprotection of a compound containing a moiety weak to an acid, decomposition is likely to occur during the deprotection. On the other hand, if a weak acid such as acetic acid or formic acid is used, deprotection to remove a TBS group may not proceed smoothly. In order to accelerate the reaction, a method of heating or increasing the concentration is available, but in such a case, a compound containing a moiety weak to an acid may sometimes be decomposed. Further, acetic acid or formic acid has a high solubility in an organic solvent and also has a high boiling point, and therefore, in a case where it is not possible to use an alkaline aqueous solution for extraction and washing after the reaction, e.g. in a case where the objective alcohol is unstable under an alkaline condition or in a case the objective compound itself is also an acid, it has a drawback such that removal of acetic acid or formic acid tends to be difficult by either method of extraction and washing or distillation under reduced pressure.
In Non-patent Document 3, formic acid is used for deprotection to remove a TBS group in a total synthesis of natural product (−)-Lankacidin C. In this case, formic acid is reacted with a TBS-protected product of allyl alcohol being an intermediate unstable to fluoride ions or hydrogen fluoride, at room temperature for 3 hours in a mixed solvent of tetrahydrofuran (THF) and water, to obtain the deprotected alcohol in a yield of 82%. However, as mentioned above, formic acid has a high solubility in an organic solvent and also has a high boiling point, and it is often difficult to remove it.
In Non-patent Document 4, periodic acid is used for deprotection of a TBS group in a total synthesis of Indolizomycin. In this case, an aqueous periodic acid solution is added to a TBS-protected product of a secondary alcohol dissolved in tetrahydrofuran (THF) and reacted therewith at room temperature for 8 hours to obtain the deprotected alcohol. However, periodic acid has an explosive nature, and in order to use it in an industrial scale, it is required to install an explosion-proof equipment. It is noted that there is a literature in which the pKa value of periodic acid in water is disclosed to be 1.6 (Non-patent Document 5), but in a subsequent literature, it has been corrected to be 3.3 (Non-patent Document 6), and in a recent book, a value of 3.3 has been adopted as the pKa (Non-patent Document 7).
In Patent Document 1, deprotection of an alcohol protected by a trimethylsilyl group which can be removed more easily than a TBS group, is carried out by means of oxalic acid which is an acid stronger than formic acid. In this document, the deprotection is carried out by reacting a compound having a plurality of hydroxyl groups protected by a TBS group and a trimethylsilyl group in the same compound, with oxalic acid in methanol at room temperature, whereby, while the trimethylsilyl group is easily removed, the TBS group is not removed. The TBS group is removed by means of TBAF or an aqueous solution of fluorosilicic acid (H2SiF6) which is an acid stronger than oxalic acid, and it is understood that a TBS group will not be removed by oxalic acid depending upon the solvent and temperature conditions.